Phosphorous Binder Equivalent Dose

Ever encountered this situation?  You're going about your daily business and discover that one of your patients on hemodialysis has an elevated phosphorous.

You skim through the list of prerequisites and see that yes, the nutritionist has been by to review dietary sources of phosphorous, the dialysis nurse has checked in on adherence to phosphorous binding medications, there's no activated vitamin D on the med list and you've explored increasing the frequency of dialysis or moving to extended nocturnal with the patient before and it's not in the cards.

Is there anything rational that can be done with the phosphorous binder dose to improve phosphorous control?  Thanks to the good work of the folks at the Frequent Hemodialysis Network (FHN) trial the answer is yes.

During the trial the investigators faced the question of whether or not changes or substitutions in multi-binder regimens represented increases or decreases in phosphorous binding capacity.  In order to answer this question the investigators combed through stool and urinary phosphorous recovery studies of individuals given various phosphate binders.   In these trials individuals were given test meals with known amounts of phosphorous.  The amount of free phosphorous appearing in the stool or urine was measured with and without binders with the difference being considered the amount of phosphorous being bound to binders in the gut.

With this information in hand the FHN group additionally looked at parallel group trials were patients on dialysis were given one of two binders and then had their doses titrated to equal serum phosphorous levels.  What emerged was a picture of the relative phosphorous binding capacity of various common binders.  Below is a table of commonly used phosphorous binders and the derived phosphate binder equivalent doses.

As you can see, all the phosphate binder equivalent doses are referenced to 1g of calcium carbonate.  So as an example, 5 tabs of 800mg sevelamer carbonate binds an equivalent amount of phosphorous (5 times 0.6 = 3) to 3 tabs of 500mg lanthanum carbonate (3 times 1.0 = 3).

Now, where ones phosphorous should ideally be is unclear (as nicely pointed out over at PBF a while back) as is the choice of agent (unless you count the realization that chronic aluminum binders where a bad deal).

Both the KDOQI and KDIGO guidelines don't endorse any one class binders over any other (again, excluding aluminum) though KDIGO gives a "2C = we suggest based on low grade evidence" that calcium based binders be restricted in the presence of arterial calcification, adynamic bone disease or persistently low PTH.  KDOQI, based on expert opinion, suggests that the amount of calcium from binders be limited to 1.5g/day (there are 200mg of calcium in a 500mg calcium carbonate tab and 169mg of calcium in a 667mg tab of calcium acetate).

Bone pain after transplant

Keeping the bone theme:

A 50-year-old woman with ESRD secondary to PKD  underwent a living related-kidney transplant one-month prior. At clinic visit, she was complaining of severe throbbing pain in her hands and feet. The pain was worse on weight bearing and exertion. Physical exam was unremarkable with no joint erythema, edema or tenderness. Her creatinine was 0.8 mg/dL and metabolic parameters were remarkable for mild hypercalcemia, nl phosphate levels, mildly increased Alk Phos and PTH of 70 pg/mL. This presentation led to this brief review of potential causes of bone pain in the transplant population.

One of the most worrisome bone complications in transplant patients is avascular necrosis. Its incidence is about 5.5% and it usually presents with hip or groin pain exacerbated by weight bearing. Diagnosis requires an MRI and more than 60% of patients that develop AVN will need a joint replacement. The bilateral nature of the pain and the involvement of feet and hands make AVN an unlikely diagnosis on this case.

Kidney transplant recipients are also at increased risk of fractures. To give you an idea, the overall fracture risk after renal transplantation is 360-380% higher than in healthy individuals and is 30% higher during the first 3 years after transplantation than in patients on dialysis. Interestingly, in one survey of 600 patients, the most common site of fracture was the foot and different than postmenopausal women, bone mineral density is not a good predictor for the risk fracture. This has to do with the inability of BMD to evaluate the quality of the bone (architecture, turnover, composition and mineralization), only measuring the density of the bone. The patient’s pain was too diffuse to be related to a fracture.

What else are we missing?
Osteomalacia caused by severe vitamin D deficiency, severe hyperparathyroidism or rapid osteopenia from high-dose corticosteroid therapy could trigger some bone pain, nonetheless her vitamin D level was normal, PTH was not very high and she had only received a short course of steroids and was steroid-free at this point.

Finally, the condition of immunosuppression-related bone marrow edema syndrome came up (also known as posttransplant bone marrow edema syndrome and calcineurin inhibitor pain syndrome). This syndrome typically presents with symmetrical pain in knees or feet associated with mildly elevated alkaline phosphatase and normal ESR/CRP. The pathophysiology is not clearly understood but it seems to be related to intra-osseous vasoconstriction. CNIs have been raised as possible culprits. A MRI imaging can usually confirm the diagnosis, showing bone marrow and periarticular soft-tissue edema and absence of avascular necrosis. Despite the possibility of severe symptoms, this condition usually regresses spontaneously, being most prevalent on the first three months after transplant. Our patient was transitioned to sirolimus without improvement. After reduction of immunossuppression, her symptoms gradually improved in the following 3 months, with associated resolution of edema on MRI.

In summary, bone pain is a common complication after transplantation and in defined cases, a MRI is required for further diagnosis, specifically to exclude avascular necrosis and possibly confirm bone marrow edema if early after transplant.

Figure: MRI showing bone marrow edema.

Better high or low bone turnover disease?

In a recent survey of 630 bone biopsy samples from patients with CKD stage 5 on dialysis, bone turnover was low in 52%, normal in 21% and high in 27% of biopsies. Defective mineralization was found in only 3%. Since the introduction of vitamin D analogs, the dominant bone disease phenotype in dialysis patients has remarkably changed. Now, adynamic bone disease is the primary bone abnormality. Since we are continuously trying to balance vit. D dose/PTH levels, I was interested in the question: if I have to choose, should I error in the side of higher or lower PTH?

I learned some interesting points about bone metabolism that I would like to share with you. When assessing bone volume abnormalities, it is important to differentiate between cortical and cancellous bone. The cortical bone, as the name implies, forms the cortex (outer shell) of most bones, being harder, stiffer and stronger than cancellous bone. It is responsible mainly for the mechanical function of the bones. On the other hand, the cancellous bone typically occurs at the ends of long bones, it has many trabeculations and is highly vascularized. Due to its high surface area, it is the predominant place of metabolic activity of the bone (e.g. exchange of calcium ions).

Now comes the interesting part. Loss of cortical bone occurs mainly in patients with high turnover bone disease, while loss of cancellous bone is often seen in patients with low bone turnover. The clinical outcome of decreased bone strength is fracture, while abnormal metabolic activity results in the inability to maintain mineral homeostasis, which is associated with vascular and soft tissue calcifications. Following these lines, adynamic bone is typically asymptomatic but it is strongly associated with hypercalcemia, cardiovascular calcifications and mortality.

What are the risk factors for adynamic bone disease?

High calcium load, low PTH and vitamin D over-treatment. Older patients, DM and peritoneal dialysis are additional associated factors.

Can we predict the type of bone disease in a dyalisis patient with PTH levels?

No, but it could give you some direction:

• Intact serum PTH values below 100 pg/mL are associated with a decreased likelihood of osteitis fibrosa and an increased incidence of adynamic bone disease.

• An intact serum PTH level above 450 pg/mL is typically associated with hyperparathyroid bone disease and/or mixed uremic osteodystrophy.

• Intermediate PTH levels between 100 and 450 pg/mL may be associated with normal, elevated bone remodeling, or even reduced bone remodeling.

Bone specific alkaline phosphatase levels could also be an adjunctive marker (below 7 ng/mL low bone turnover, above 20 high bone turnover). Radiographic examination of bone can provide important information regarding the presence of hyperparathyroidism (such as subperiosteal resorption). However, radiographic findings are less sensitive than PTH levels and will not establish the type of bone disease. The gold standard is bone bx.

When should you perform a bone bx?

Controversial topic but a bx could be considered in the setting of unexplained fractures, unexplained hypercalcemia, and/or unexplained hypophosphatemia; persistent bone pain; possible aluminum toxicity; and before therapy with bisphosphonates.

How should adynamic bone be treated?

Lower PTH levels should be treated by decreasing the doses of calcium-based phosphate binders, vitamin D, a low dialysate calcium concentration, and perhaps by the use of non-calcium-based phosphate binders (though no data yet supporting this).

My feeling is that we should be cautious in the administration of vitamin D and adjust with small increments based on PTH levels, especially due to the metabolic complications of adynamic bone and difficulty to reverse it. Adynamic bone disease is a relative new entity and long-term complications have not been fully determined yet. I must confess that since PTH does not truly predict the type of bone disease, it is a hell of an empirical area...

A new drug for bone loss in renal patients?

At a recent meeting on bone biology, several talks were devoted to a new class of drugs targeting osteoporosis. Since these drugs are antibodies and thus not cleared by the kidney, I paid close attention, as they have the potential to be useful in patients with renal failure, where we generally shun bisphosphonates.


But first, lets talk about bone remodeling (see also this tutorial). Bone constantly remodels through a delicate interplay between two types of cells on the bone surface: the bone-producing osteoblasts, and the bone-resorbing osteoclasts (One source suggests that approximately 10% of the adult skeleton turns over every year). Osteoclasts are activated in part by a signal made by osteoblasts called RANKL (receptor activator of NFkB ligand), which binds to its receptor on osteoclasts. Once activated, osteoclasts start resorbing bone by acidifying the section of bone immediately underneath them (called a resorptive pit) to help digest and release the protein matrix (mostly collagen) and free up calcium and phosphate.


Denosumab, sold under the tradename Prolia by Amgen (FDA approved June 2010), is a monoclonal antibody against RANKL. It thus prevents activation of osteoclasts and the initiation of resorption. Denosumab is given every six month subcutaneously. In a randomized trial (The Freedom trial), which enrolled over 7800 women between the ages of 60 and 90 with a T score on their dexa scan between -2.5 and -4.0, denosumab prevented the radiological evidence of vertebral fractures (primary endpoint), as well as reduced the risk of hip fractures and non-vertebral fractures, increased bone mineral density at the lumbar spine and hip, and did so with minimal adverse effects.


No patients with ESRD were included, though a stratification of patients based on renal function reveals 74 patients with CrCl 15-29 (avg Cr 1.5+/-0.3), 2817 patients with CrCl of 30-59 (avg Cr 0.9) and 4059 with CrCl 60-89 (avg Cr 0.8). Comparing the patients with severe renal impairement to those with mild, the first set of women were older (80 vs 71 yo), thinner (avg weight 53 vs 66 kg) and had worse femoral neck and hip BMD T scores (-2.8 vs -2.1 and -2.8 vs -1.8). Despite this perhaps less healthy population, the primary endpoint, radiological vertebral fractures, was reduced in this sub-group as well, with an incidence of 9.1% in the placebo group vs 3.2% in the active drug.


One major issue with this drug in this sub-group, was the increased incidence of serious infections: 11 in the denosumab group (31 pts received the drug, so the rate was ~30%) vs 4 in the placebo group (33 patients received placebo, for a rate of 12%). It appears that the infections are mostly cellulitis. While this difference was not statistically significant, it would give me pause. Given that the population in this trial was probably “healthier” (Calcium had to be normal for study entry; PTH was not checked), I think more data is needed before we can consider denosumab safe in patients with renal dysfunction.

Re-Evaluating the Ca x P Product

Heard an excellent presentation at our Renal Grand Rounds today by Dr. Charles O'Neill of Emory University, regarding the process of pathologic calcification in CKD/ESRD patients.

One of the points I took away from this talk is that we need to re-evaluate the role of the "calcium-phosphate product" in clinical medicine.  Presently, the KDOQI guidelines state that nephrologists should attempt to maintain the Ca x P product below 55 in order to minimize pathologic calcification.  I had always been taught that if the Ca x P product exceeds 55, there is a tendency for calcium phosphate to precipitate and deposit within the walls of blood vessels.  Is this true?

This 20007 KI review ("The Fallacy of the calcium-phosphorus product") makes the case that this view is erroneous.  The majority of medial calcification seen in CKD/ESRD patients is in the form of hydroxyapatite, which is much more complex than calcium phosphate; the chemical structure is Ca10(PO4)6(OH)2.  As the formation of hydroxyapatite involves multiple separate steps, it is very unlikely to occur spontaneously. A more likely scenario is that a local balance between specific calcification inhibitors (e.g., pyrophosphate) and activators (e.g., alkaline phosphatase) maintained at a local level determines whether or not pathologic calcification occurs.  Furthermore, experiments in which exogenous calcium and phosphate were added to samples of human plasma  demonstrated that calcium-phosphate precipitation did not occur until the Ca x P product exceeded over 200--a number which is never achieved in human patients.  

Nonetheless, despite these potential flaws in the physiologic rationale for the Ca x P product, there is abundant epidemiologic evidence showing an association between the Ca x P product and cardiovascular mortality.  Perhaps this simply reflects the observation that serum calcium and serum phosphate levels each independently potentially contribute to pathologic calcification.  In any case, the prevailing current approach is to control serum phosphate levels with binders to within the normal range as much as possible while tolerating some degree of mild hypocalcemia.  

Sensipar for APKD?

Following on the heels of studies showing a potentially beneficial effect for vasopressin receptor antagonists and rapamycin in the treatment of renal cystic disorders, an article in this month's JASN by Gattone et al suggests another class of commonly-used nephrology-related drug which may be of use: calcimimetics (such as cinacalcet, or sensipar).

The logic is as follows: The growth of cysts in PKD is thought to be driven by low intracellular calcium levels and elevated cAMP levels. The calcium sensing receptor (upon which cinacalcet acts) is activated by binding to serum ionized calcium, and results in a G-protein-mediated decrease in cAMP levels & increase in intracellular calcium concentration. The investigators therefore suggested that cinacalcet might be an effective way to reduce cyst growth in late PKD.

To test their hypothesis, they took a rat model of PKD (Cy/+) and treated them either with placebo or with the calcimimetic R-568, which is similar in function to cinacalcet. Interestingly, rats in the treatment group showed less advanced cyst formation and fibrosis at later time points, suggesting that their hypothesis may be correct. This study is somewhat unique in that it looks at fairly advanced stages of cystic kidney disease, whereas other animal studies have focused on a more prophylactic approach to cyst growth.

Cautious optimism for ADPKD patients--if I were a young guy with the PKD1 or PKD2 gene, I would seriously consider enrollment in one of the ongoing trials.

Lithium-Induced Hyperparathyroidism

Lithium, a very effective medication in the treatment of bipolar disorder, has a variety of well-documented renal side effects, including interstitial nephritis and nephrogenic diabetes insipidus.  A less well-recognized complication is an increased prevalence of hyperparathyroidism in chronic lithium users.

Individuals with chronic Li use frequently have both elevated calcium levels as well as elevated PTH levels, and it can be very difficult to differentiate from primary hyperparathyroidism or familial idiopathic hypercalciuria.  The mechanisms for why patients on Li therapy have these lab abnormalities is still up for debate, but this interesting article describes three potential mechanisms:  first, Li has been shown to block Ca2+ influx into a variety of cells by competitive inhibition of Ca2+ transport across the cell membrane.  The elevated ionized Ca2+ would then drive up PTH levels.  In addition, there is some evidence that Li raises the threshold of the Ca-sensing receptor in parathyroid cells, and increased Ca2+ levels are necessary to keep PTH secretion under check.  Finally, it is postulated that Li directly increases PTH transcription by virtue of its inhibitory effects on the enzyme glycogen synthase kinase 3b (GSK-3b), a known transcriptional repressor of PTH mRNA.  

By the way, I learned today that Lithium is reabsorbed in the kidney via both the Na/H antiporter in the proximal tubule as well as ENac in the collecting duct.  Therefore diuretics which block these transport mechanisms (e.g., amiloride) can have a dramatic lithium-lowering effect when acutely given to somebody on chronic Lithium.  

Vitamin D Basics

Sometimes the formulations of vitamin D can get confusing. Here's a few key points:

1. The terms "vitamin D2" and "vitamin D3" do not refer to the hydroxylation status of vitamin D--either D2 or D3 can exist in the (1,25-OH), (25-OH), and unhydroxylated varieties--rather, they refer to whether or not the vitamin D derives from animal (D3, also called cholecalciferol) or plant (D2, also called ergocalciferol).

2. Ergocalciferol (Vit D2) is the least expensive, is the type of vitamin D with which milk is fortified, and can be given in large enough oral doses to correct vitamin D deficiency relatively rapidly (e.g., 50000 units of ergocalciferol po qweek x 12 weeks).

3. Cholecalciferol (Vit D3) is better absorbed orally than Vit D2, but is not available as a high dose form like D2 (e.g., 400-800 units po qd of cholecalciferol).

4. Calcitriol refers to the activated form of vitamin D, which is hydroxylated at both the (1) and (25) positions, and may be either D2 or D3; the medication calcitriol is the D3 form.

5. Cholecalciferol (VitD3) is produced in the human skin in response to UV light and is initially unhydroxylated at both the (1) and (25) position. Hydroxylation occurs at the (25) position in the liver (an efficient process which generally occurs even in the setting of advanced liver disease) and occurs at the (1) position in the kidney.

6. Paricalcitol (Zemplar) is a vitamin D2 analogue which is hydroxylated at both (1) and (25) positions.

7. doxercalciferol (Hectorol) is another vitamin D2 analogue which is hydroxylated only at the (1) position.

Adynamic bone disease

Adynamic bone disease is being increasingly recognized as the most common form of renal osteodystrophy. It is characterized by the reduced synthesis of bone matrix due to decreased osteoblastic and osteoclastic activity. Adynamic bone disease is distinct from osteomalacia, in which osteoid (the bone protein matrix, composed primarily of type I collagen) accumulates due to a lack of osteoblast activity or defective osteoid mineralization, as opposed to the simple decreased rate of turnover seen in adynamic bone disease.

Adynamic bone disease is particularly common in the peritoneal dialysis population in that the constant exposure to calcium in the dialysate fluid leads to episodic hypercalcemia and suppression of PTH levels which results in adynamic bone. A 2006 study by Haris et al in Kidney International randomized PD patients with adynamic bone disease (as assessed by bone biopsy) to normal Ca (1.62mM) versus low Ca (1.0mM) dialysate. The low-Ca dialysate group developed a higher PTH and bone turnover rates within the normal range, suggesting that the low Ca dialysate strategy is a good one for PD patients in order to avoid adynamic bone.

DCOR Trial

The DCOR Trial was a Genzyme-funded randomized control trial--somebody recently told me the largest ever conducted in a dialysis population--designed to compare the phosphate binder sevelamer (Renagel) with Ca-containing phosphate binders (calcium acetate a.k.a. Phoslo or calcium carbonate). The theory behind the trial is that since cardiovascular disease is the #1 killer of ESRD patients, and since vascular calcifications are hypothesized to cause accelerated atherosclersosis, then a non-calcium-containing phosphorus binder such as sevelamer would be expected to not contribute as much to vascular calcifications and cardiovascular disease.

Sounds good, but the primary end-point of mortality was identical in the two groups. In "sub-group analysis", there was allegedly a trend towards benefit in the sevelamer group in those >65 years of age or those who had been taking the medication for >2 years, but overall there seems to be a consensus that this represents a negative trial.

In related news, sevelamer costs significantly more than calcium acetate (and certainly more than calcium carbonate for that matter). You make the call as to which phosphate binder is better for your patients...

FGF23

For many years, the existence of "phosphatonins"--substances secreted by certain tumors which result in profound renal phosphorus wasting and resultant osteomalacia--has been postulated.

Evidence has recently been accumulating that fibroblast growth factor 23 (FGF-23) is the phosphatonin we have been searching for:

High circulating levels of FGF23 are associated with hypophosphatemia, decreased 1,25 (OH) vitamin D levels, and rickets/bone disease.

The disease autosomal dominant hypophosphatemic rickets is caused by gain-of-function mutations in FGF23caused by splice site mutations. Conversely, the genetic disease inherited tumoral calcinosis, characterized by hyperphosphatemia, increased 1,25 (OH) vitamin D levels, and metastatic calcifications.

In ESRD, FGF23 levels are appropriately elevated in response to hyperphosphatemia, but due to a reduced GFR is unable to induce adequate phosphaturia.

How it works at a molecular level: FGF23 interacts with FGF receptors at the proximal tubule, resulting in decreased Na-PO4 exchange, as well as decreasing 1,25-alpha hydroxylase activity.